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  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
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  • B01J31/2208—Oxygen, e.g. acetylacetonates
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  • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
  • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
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  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/4015—Esters of acyclic unsaturated acids
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/4018—Esters of cycloaliphatic acids
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  • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
  • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
  • B01J2231/32—Addition reactions to C=C or C-C triple bonds
  • B01J2231/323—Hydrometalation, e.g. bor-, alumin-, silyl-, zirconation or analoguous reactions like carbometalation, hydrocarbation
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  • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
  • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
  • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
  • B01J2231/341—1,2-additions, e.g. aldol or Knoevenagel condensations
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  • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
  • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
  • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
  • B01J2231/348—1,4-additions, e.g. conjugate additions
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  • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
  • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
  • B01J2531/0266—Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
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  • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
  • B01J2531/11—Lithium
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  • B01J2531/30—Complexes comprising metals of Group III (IIIA or IIIB) as the central metal
  • B01J2531/31—Aluminium

Definitions

• the present invention relates to a metal complex which can be used in the preparation of an asymmetric compound useful in the fields of medicines, agricultural chemicals, perfumes, liquid crystals, and the like. More particularly, it relates to a metal complex by which an optically active reaction product having high optical purity can be obtained in high yield when it is used as a catalyst for asymmetric Michael addition reaction, asymmetric hydrophosphonylation reaction, or the like, as well as a process for producing an asymmetric compound using a solution of the metal complex.
• the present inventors previously studied an asymmetric synthesis reaction using a metal complex catalyst of a rare earth metal element and, as a result, found that a metal complex prepared by a method of mixing lanthanum chloride (LaCl 3 ) and optically active dilithium binaphthoxide in tetrahydrofuran and adding water and sodium hydroxide thereto, or by a method of successively adding optically active binaphthol, water, and lithium chloride to a solution of La 3 (O-tC 4 H 9 ) 9 (lanthanum t-butoxide) in tetrahydrofuran containing sodium tert-butoxide, can catalyze an asymmetric nitroaldol reaction to afford a nitroaldol product having high optical purity (J. Am. Chem. Soc., Vol. 114, p. 4418 (1992)).
• La 3 (O-tC 4 H 9 ) 9 lanthanum t-butoxide
• a metal complex i.e., La--K-Binol (LPB)
• LPB La--K-Binol
• La--Li-Binol (LnLB)
• LnLB La--Li-Binol
• lanthanum which is a rare earth metal element contained in the aforementioned metal complexes, is difficult to obtain and, thus, the development of metal complex catalysts without using a rare earth metal is desired.
• metal complex catalysts are not yet known.
• an asymmetric Michael reaction product and an asymmetric ⁇ -hydrophosphonylated compound are both known as useful asymmetric compound reaction products.
• a hydroxy phosphorylated compound has potent bioactivity and is expected to act effectively as an enzyme inhibitor for a synthesis enzyme such as renin, EPSP synthase, HIV protease, and the like and, thus, the development of an optically selective process for synthesizing these asymmetric phosphorylated compounds is desired.
• Ln--Li-Binol Ln--Li-Binol
• the present invention provides a metal complex, or a solution of the metal complex, that can be used as a catalyst in an asymmetric Michael reaction and in an asymmetric hydrophosphonylation reaction, contains no rare earth metal element, and can afford an optically active compound having high optical purity at high yield.
• the present invention also provides a process for producing an asymmetric compound by an asymmetric Michael reaction and an asymmetric hydrophosphonylation reaction using such the metal complex.
• the present inventors further studied an asymmetric synthesis catalyst using optically active binaphthol and a derivative thereof and found that, although the chemical structure is not clear, a metal complex prepared using an aluminum compound, without using a rare earth metal compound, acts as an extremely effective catalyst in the asymmetric Michael reaction and the asymmetric hydrophosphonylation reaction, and produces, at high yield, a Michael adduct and an asymmetric hydrophosphonylated compound having high optical purity.
• a metal complex of the present invention is characterized by the fact that it can be obtained by reacting optically active binaphthol, or a derivative thereof, with an alkali metal aluminum hydride or an alkali metal aluminum hydride compound.
• a metal complex of the present invention is characterized by the fact that it can be obtained by reacting optically active binaphthol, or a derivative thereof, with dialkylaluminum hydride, and a base containing an alkali metal or a base containing an alkaline earth metal.
• optically active binaphthol or derivative thereof that can be used for preparing a metal complex of the present invention
• a compound represented by the following general formula 1 can be used:
• R 1 , R 2 , R 3 , and R 4 are, independently, a group selected from the group consisting of a hydrogen atom, a lower alkyl group, a lower alkoxy group, halogen, cyano, and nitro.
• R 1 to R 4 can be the same or different from each other.
• alkali metal aluminum hydride that can be used in preparation of a metal complex of the present invention
• lithium aluminum hydride is a typical example.
• alkali metal aluminum hydride compound which can be used in preparation of a metal complex of the present invention a compound that can be easily obtained, such as sodium-bis(methoxyethoxy) aluminum hydride, diisobutylaluminum hydride, and the like can be used.
• a preferable molar ratio of the optically active binaphthol or a derivative thereof and the alkali metal aluminum hydride in the preparation of a metal complex is in a range of 1-4:1, preferably 1.5-2.5:1, and more preferably 2:1.
• dialkylaluminum hydride that can be used in the preparation of a metal complex of the present invention, there are diethylaluminum hydride, diisopropylaluminum hydride, diisobutylaluminum hydride, and the like. From among them, diisobutylaluminum hydride is preferably used.
• the base containing an alkali metal there are sodium methylate, sodium ethylate, sodium isopropoxide, sodium tert-butoxide, lithium hydride, potassium hydride, sodium borohydride, lithium tert-butoxide, butyllithium, and the like. From among them, sodium tert-butoxide is preferably used.
• the base containing an alkaline earth metal barium tert-butoxide and the like can be used.
• An equivalent ratio of the optically active binaphthol or a derivative thereof, the dialkylaluminum hydride, and the base containing an alkali metal or an alkaline earth metal is 1-4:0.5-2:1. The use at an equivalent ratio of 1.5-2.5:0.5-1.5:1 is preferable and the use at an equivalent ratio of 2:1:1 is more preferable.
• organic solvents can be used in the preparation of the above metal complex.
• ethereal solvents are preferable. From among them, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, and mixtures thereof are particularly preferable, although solvents such as toluene, hexane, heptane, and the like can be used.
• An organic solution, in which a metal complex is prepared, can be used as such for synthesizing an asymmetric compound without isolation of the metal complex therefrom.
• the metal complex of the present invention can be suitably used in an asymmetric Michael reaction and is particularly useful in a reaction of cyclopentenone or cyclohexenone with a malonic diester or an alkylmalonic diester.
• an optically active compound having the following general formula 2 can be obtained by adding an aliphatic or an aromatic aldehyde thereto.
• R 1 is a residue of an aliphatic compound or an aromatic compound
• R 2 is hydrogen or an alkyl group
• R 3 is an alkyl group or an aralkyl group.
• the metal complex of the present invention can be suitably used in an asymmetric hydrophosphonylation reaction.
• a reaction solvent for performing this asymmetric hydrophosphonylation reaction is not limited to specified solvents, and preferably is benzene, toluene, or xylene.
• the process for producing an asymmetric hydrophosphonylated compound of the present invention can be suitably used to obtain an asymmetric hydrophosphonylated compound shown by the following general formula 5 by reacting an aldehyde shown by the following general formula 3 with a phosphonic diester compound shown by the following general formula 4.
• R 1 is a hydrogen atom, a halogen atom, an alkyl group having 1-4 carbon atoms, an alkoxy group having 1-4 carbon atoms, a nitro group, an amino group, an alkylamino group, or a dialkylamino group
• R 2 is an alkyl group having 1-8 carbon atoms, an arylalkyl group, or a silylalkyl group.
• the symbol * represents an asymmetric carbon atom.
• an asymmetric hydrophosphonyl compound of the present invention can be suitably used to obtain an asymmetric hydrophosphonyl compound shown by the following general formula 8 by reacting an aldehyde shown by the following general formula 6 with a phosphonic diester compound shown by the following general formula 7.
• R 3 , R 4 , and R 5 are, independently, a hydrogen atom, a phenyl group, a lower alkyl-substituted phenyl group, a lower alkoxy-substituted phenyl group, or an alkyl group or an alkoxy group each having 1-8 carbon atoms, or R 3 and R 4 , or R 4 and R 5 , can form a ring.
• R 6 is an alkyl group having 1-8 carbon atoms, an arylalkyl group, or a silylalkyl group, and the symbol * represents an asymmetric carbon atom.
• an asymmetric hydrophosphonyl compound of the present invention can be suitably used to obtain an asymmetric hydrophosphonyl compound shown by the following general formula 11 by reacting an aldehyde shown by the following general formula 9 with a phosphonic diester compound shown by the following general formula 10.
• R 1 is a linear or branched alkyl group having 1-8 carbon atoms, or a cyclic alkyl group having 3-10 carbon atoms.
• R 2 is an alkyl group having 1-8 carbon atoms, an arylalkyl group, or a silylalkyl group, and the symbol * represents an asymmetric carbon atom.
• the asymmetric hydrophosphonylation reaction can be carried out at the temperature of -70° C. to 45° C.
• the reaction temperature preferably is -20° C. to -60° C., more preferably -30° C. to -45° C., and most preferably -40° C.
• various organic solvents can be used. From among them, aromatic hydrocarbons such as xylene, toluene, benzene, and mixtures thereof are particularly preferable. However, aliphatic hydrocarbons, such as hexane, heptane, and the like, ether compounds, such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, and the like can be used.
• aromatic hydrocarbons such as xylene, toluene, benzene, and mixtures thereof are particularly preferable.
• aliphatic hydrocarbons such as hexane, heptane, and the like
• ether compounds such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, and the like can be used.
• Lithium aluminum hydride (114 mg, 3.0 mmol) was dissolved in anhydrous tetrahydrofuran (15 ml) under an argon atmosphere. To this solution was added, dropwise, a solution of (R)-binaphthol in anhydrous tetrahydrofuran (1.72 g, 6.0 mmol/THF 15 ml) at 0° C., which was stirred at room temperature for 12 hours. The supernatant was used as a solution of Al--Li--(R)-binaphthol complex in tetrahydrofuran (0.1M).
• Example 2 The same procedure as shown in Example 1 was used, except that (R)-6,6'-dibromobinaphthol (obtained from Kankyokagaku Center Co., Ltd.) was used in place of the (R)-binaphthol of Example 1 to afford Al--Li--(R)-6,6'-dibromobinaphthol.
• (R)-6,6'-dibromobinaphthol obtained from Kankyokagaku Center Co., Ltd.
• a process for synthesizing (R)-6,6'-dibromobinaphthol is shown below.
• Example 13 the workup was performed as in Example 13 to obtain the three component combination compound of a final product in a yield of 82%.
• the product was oxidized with pyridinium chlorochromate (hereinafter abbreviated as PCC) to obtain the diketone compound as shown in chemical formula 25.
• PCC pyridinium chlorochromate
• Table 11 the optical purity of the diketone compound was 89% e.e. Therefore, it is considered that the optical purity of the three-component combination-type reaction product in this Example is also 89% e.e.
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Benzaldehyde (0.40 mmol) then was added thereto. After reacting for 51 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml ⁇ three times).
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then p-chlorobenzaldehyde (0.40 mmol) was added thereto. After reacting for 38 hours, 1N hydrochloric acid was added thereto to stop the reaction.
• dimethyl phosphite 37 ⁇ l, 0.40 mmol
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then p-methylbenzaldehyde (0.40 mmol) was added thereto. After reacting for 92 hours, 1N hydrochloric acid was added thereto to stop the reaction.
• dimethyl phosphite 37 ⁇ l, 0.40 mmol
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring for 30 minutes at room temperature, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then, p-methoxybenzaldehyde (0.40 mmol) was added thereto. After reacting for 115 hours, 1N hydrochloric acid was added thereto to stop the reaction.
• dimethyl phosphite 37 ⁇ l, 0.40 mmol
• Dimethyl phosphite (37 ⁇ l, 0.40 mmol) was added to the solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -78° C., and it was maintained at this temperature for 15 minutes. Then p-nitrobenzaldehyde (0.40 mmol) was added thereto. After the temperature was raised to room temperature, the stirring was continued for 12 hours. Hydrochloric acid (1N) was added thereto to stop the reaction, and the mixture was extracted with ethyl acetate (10 ml ⁇ three times). The combined extracts were washed with brine and dried over Na 2 SO 4 .
• Dimethyl phosphite (37 ⁇ l, 0.40 mmol) was added to the solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. p-Dimethylaminobenzaldehyde (0.40 mmol) was added thereto. After reacting for 48 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml ⁇ three times), and the combined mixture were washed with brine and dried over Na 2 SO 4 .
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added diethyl phosphite (0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then, benzaldehyde (0.40 mmol) was added thereto. After reacting for 90 hours, 1N hydrochloric acid was added thereto to stop the reaction.
• Example 26 The same procedure as shown in Example 26 was used, except that dibutyl phosphite was used in place of the diethyl phosphite used in Example 26 to afford dibutyl (S)-hydroxy-phenylmethylphosphonate as a final product in a yield of 42%.
• Example 26 The same manner as shown in Example 26 was adopted except that dibenzyl phosphite was used in place of diethyl phosphite used in Example 26 and that the reaction was performed at room temperature for 6.5 hours to afford dibenzyl (S)-hydroxy-phenylmethylphosphonate of a final product in a yield of 60%.
• the analysis results on this reaction product are shown in Table 22.
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then, cinnamaldehyde (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction.
• dimethyl phosphite 37 ⁇ l, 0.40 mmol
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes, then (E)- ⁇ -methylcinnamaldehyde (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction.
• dimethyl phosphite 37 ⁇ l, 0.40 mmol
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then 3-methyl-2-butenal (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction.
• dimethyl phosphite 37 ⁇ l, 0.40 mmol
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then 2-hexenylaldehyde (0.40 mmol) was added thereto. After reacting for 39 hours, 1N hydrochloric acid was added thereto to stop the reaction.
• dimethyl phosphite 37 ⁇ l, 0.40 mmol
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then (E)- ⁇ -methylcinnamaldehyde (0.40 mmol) was added thereto. After reacting for 61 hours, 1N hydrochloric acid was added thereto to stop the reaction.
• dimethyl phosphite 37 ⁇ l, 0.40 mmol
• Example 33 The same procedure as shown in Example 33 was used, except that 2-methylpropenal was used in place of the (E)- ⁇ -methylcinnamaldehyde (0.40 mmol) used in Example 33 and that the reaction was carried out for 35 hours to afford dimethyl (S,E)-1-hydroxy-2-methyl-2-propenylphosphonate as a final product in a yield of 65%.
• the chemical reaction in this Example 15 is shown in chemical formula 39.
• Example 33 The same procedure as shown in Example 33 was used, except that cyclohexylidene- ⁇ 1 ⁇ -acetaldehyde was used in place of the (E)- ⁇ -methylcinnamaldehyde (0.40 mmol) used in Example 33 and the reaction was carried out for 47 hours to afford dimethyl-(S)-cyclohexylidene- ⁇ 1 ⁇ -1-hydroxyethylphosphonate in a yield of 65%.
• the chemical reaction in this Example is shown in chemical formula 40.
• Example 2 The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then 2-methylpropionaldehyde (0.40 mmol) was added thereto. After reacting for 38 hours, 1N hydrochloric acid was added thereto to stop the reaction.
• dimethyl phosphite 37 ⁇ l, 0.40 mmol
• Example 36 The same procedure as shown in Example 36 was used, except that hexanal was used in place of the 2-methylpropionaldehyde used in Example 36 and the reaction was carried out for 20 hours to afford dimethyl (S)-1-hydroxyhexylphosphonate as a final compound in a yield of 90%.
• the chemical reaction in this Example is shown in chemical formula 42.
• Example 36 The same procedure as shown in Example 36 was used, except that cyclohexanal was used in place of the 2-methylpropionaldehyde used in Example 36 and the reaction was carried out for 43 hours to afford dimethyl (S)-1-hydroxyhexyl phosphonate in a yield of 91%.
• the chemical reaction in this Example is shown in chemical formula 43.
• Asymmetric hydrophosphonylation reaction using Al--Li--(R)-6,6'-dibromobinaphthol hereinafter abbreviated as ALB--Br
• Example 4 The solution of ALB--Br in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 4 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol). After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then benzaldehyde (0.40 mmol) was added thereto. After reacting for 59 hours, 1N hydrochloric acid was added to stop the reaction.
• Example 39 The same procedure as shown in Example 39 was used, except that p-methoxybenzaldehyde was used in place of the benzaldehyde used in Example 39 to afford dimethyl (S)-hydroxy(p-methoxyphenyl)methylphosphate as a final product in a yield of 72%.
• the chemical reaction in this Example is shown in chemical formula 45.
• Asymmetric hydrophosphonylation reaction using Al--Li--(R)-6,6'-dicyanobinaphthol hereinafter abbreviated as ALB--CN
• Example 5 The solution of ALB--CN in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 5 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 ⁇ l, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then p-methoxybenzaldehyde (0.40 mmol) was added thereto. After reacting for 59 hours, 1N hydrochloric acid was added to stop the reaction.
• dimethyl phosphite 37 ⁇ l, 0.40 mmol
• Example 41 The same procedure as shown in Example 41 was used, except that 2-methylpropionaldehyde was used in place of the p-methoxybenzaldehyde used in Example 41 to afford dimethyl (S)-1-hydroxy-2-methylpropylphosphonate as a final product in a yield of 66%.
• the chemical reaction in this Example is shown in chemical formula 47.
• Example 41 The same procedure as shown in Example 41 was used, except that 3-methyl-2-butenal was used in place of the p-methoxybenzaldehyde used in Example 41 to afford dimethyl (R)-1-hydroxy-3-methyl-2-butenylphosphonate as a final product in a yield of 34%.
• the chemical reaction in this Example is shown in chemical formula 48.
• the process for producing an asymmetric compound of the present invention is suitable for obtaining, in a high yield, an optically active compound having high optical purity, which is useful as an intermediate for medicines, by an asymmetric Michael reaction and an asymmetric hydrophosphonylation reaction although the process uses, as a catalyst, a metal complex containing no rare earth metal element.

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